Histone Deacetylase Inhibition in Prostate Cancer Triggers miR-320-Mediated Suppression of the Androgen Receptor
Histone Deacetylase Inhibition in Prostate Cancer Triggers miR-320-Mediated Suppression of the Androgen Receptor
复制标题
DOI：
10.1158/0008-5472.can-15-3339
复制
发表时间：
2016-07-15
期刊：
影响因子：
11.2
通讯作者：
Kondo, Yutaka
中科院分区：
文献类型：
--
作者：
Sato, Shinya;Katsushima, Keisuke;Kondo, Yutaka
针对雄激素受体（AR）进行药物干预是治疗恶性前列腺癌的有效途径之一。组蛋白去乙酰化酶（HDAC）改变肿瘤相关基因的表观遗传状态，包括miRNA基因，并影响癌症的行为。在这里，我们研究了HDAC抑制剂OBP-801对前列腺癌中AR表达和肿瘤细胞生长的分子效应。OBP-801有效抑制三种前列腺癌细胞系（22Rv1、VCaP和LNCaP）的细胞生长，并下调AR，无论其激素敏感性如何。有趣的是，OBP-801的这种作用不是由于AR基因的转录活性降低，而是由于转录后调控，即mirna介导的抑制。在三种前列腺癌细胞系中，经OBP-801处理后表达上调的mirna中，miR-320a与AR表达最为密切，其表达与前列腺癌预后显著相关（P = 0.0185）。miR-320a模拟物抑制AR蛋白表达并抑制生长，而anti-miR-320a寡核苷酸显著消除OBP-801处理的生长抑制。FISH分析显示，miR-320a在人正常前列腺腔细胞中高表达，但在前列腺癌细胞中很少表达。在ar依赖性前列腺肿瘤大鼠模型中，OBP-801治疗可显著提高miR-320a的表达并抑制前列腺肿瘤的发生。我们的数据表明，OBP-801通过表观遗传上调miR-320a有效抑制AR活性，从而抑制前列腺癌的肿瘤细胞生长。无论雄激素依赖性如何，OBP-801可能是ar阳性前列腺癌的有效ar靶向治疗试剂。AACR (C) 2016人。
Targeting androgen receptor (AR) by pharmacologic intervention is one of the effective approaches for treatment of malignant prostate cancers. Histone deacetylase (HDAC) alters the epigenetic status of tumor-associated genes, including those for miRNAs (miRNA), and affects the behavior of cancers. Here, we examined the molecular effects of a HDAC inhibitor, OBP-801, on AR expression and tumor cell growth in prostate cancers. Treatment with OBP-801 efficiently suppressed cell growth of three prostate cancer lines (22Rv1, VCaP, and LNCaP), together with AR downregulation, regardless of their hormone sensitivity. Intriguingly, this effect by OBP-801 was not due to decreased transcriptional activity of the AR gene, but due to posttranscriptional regulation, namely by miRNA-mediated suppression. Among the upregulated miRNAs after OBP-801 treatment in the three prostate cancer cell lines, miR-320a, whose expression was significantly correlated with prognosis of prostate cancers (P = 0.0185), was the most closely associated with AR expression. An miR-320a mimic suppressed AR protein expression together with growth suppression, while anti-miR-320a oligonucleotide significantly abrogated the growth suppression by OBP-801 treatment. FISH analysis revealed that miR-320a was highly expressed in human normal prostate luminal cells, but was rarely expressed in prostate cancer cells. In an AR-dependent prostate tumorigenic rat model, OBP-801 treatment profoundly increased miR-320a expression and repressed prostate tumorigenesis. Our data demonstrated that OBP-801 effectively suppressed AR activity via epigenetic upregulation of miR-320a, which resulted in tumor cell growth suppression of prostate cancers. OBP-801 may be a potent AR-targeting therapeutic reagent in AR-positive prostate cancer regardless of androgen dependency. (C)2016 AACR.